Pharmaceutical piperazine compounds

ABSTRACT

A piperazinedione of general formula (I): ##STR1## wherein R 1  is selected from hydrogen; 
     a group of formula --(NH) t  --COR 3  wherein t is 0 or 1 and R 3  is an organic substituent as defined herein; 
     a group of formula (D): ##STR2##  and a group of formula (E): ##STR3## and the pharmaceutically acceptable salts thereof are useful as modulators of multi-drug resistance.

The present invention relates to compounds useful as modulators ofmulti-drug resistance (MDR), to their preparation and to pharmaceuticaland veterinary compositions containing them.

The resistance of tumours to treatment with certain cytotoxic agents isan obstacle to the successful chemotherapeutic treatment of cancerpatients. A tumour may acquire resistance to a cytotoxic agent used in aprevious treatment. A tumour may also manifest intrinsic resistance, orcross-resistance, to a cytotoxic agent to which it has not previouslybeen exposed, that agent being unrelated by structure or mechanism ofaction to any agent used in previous treatments of the tumour.

Analogously, certain pathogens may acquire resistance to pharmaceuticalagents used in previous treatments of the diseases or disorders to whichthose pathogens give rise. Pathogens may also manifest intrinsicresistance, or cross resistance, to pharmaceutical agents to which theyhave not previously been exposed. Examples of this effect includemulti-drug resistant forms of malaria, tuberculosis, leishmaniasis andamoebic dysentery.

The above phenomena are referred to collectively as multi-drugresistance (MDR). As discussed more fully later on, a plasma membraneglycoprotein (P-gp) is implicated in the mechanism which underlies MDR.P-gp has drug binding properties. Certain agents which have the capacityto modulate MDR may therefore also be useful in facilitating thedelivery of drugs across the blood-brain barrier and in treating AIDSand AIDS-related complex.

Disadvantages of drugs which have so far been used to modulate MDR,termed resistance modifying agents or RMAs, are that they frequentlypossess a poor pharmacokinetic profile and/or are toxic at theconcentrations required for MDR modulation.

It has now been found that a series of piperazinedione derivatives haveactivity as modulators of multi-drug resistance. The present inventiontherefore provides a piperazinedione derivative of formula (I): ##STR4##wherein R¹ is selected from: hydrogen;

a group of formula --(NH)_(t) --COR³ wherein t is 0 or 1 and R³ isselected from: ##STR5## wherein v is 0 when t is 1 and v is 1 when t is0; and wherein n is 0 or 1 and m is 0, 1, 2 or 3, at least one of n andm being other than 0, and either:

(a) R⁴ is H or C₁ -C₆ alkyl and R⁵ is C₁ -C₆ alkyl optionallysubstituted by one or two phenyl groups, the phenyl group or groupsbeing optionally substituted by one or two C₁ -C₆ alkoxy groups; or

(b) R⁴ and R⁵, together with the nitrogen atom to which they areattached, form a heterocyclic group selected from (1) to (4): ##STR6##wherein R⁶ and R⁷, which are the same or different, are H or C₁ -C₆alkoxy or R⁶ and R⁷ form together a methylenedioxy group; Y is 0 or--NR⁸ wherein R⁸ is C₁ -C₆, alkyl or a phenyl group optionallysubstituted by CF₃ ;

    --NH--(CH.sub.2).sub.p --Z                                 (B)

wherein p is 1 or 2 and Z is C₂ -C₆ alkenyl or a phenyl group optionallysubstituted by C₁ -C₆ alkoxy; and ##STR7## wherein R⁹ is C₁ -C₆ alkyl,pyrimidinyl or a phenyl group optionally substituted by C₁ -C₆ alkoxy;and ##STR8## wherein w is 1, 2 or 3 and L is a heterocyclic group offormula (1) as defined above;

a group of the formula (D): ##STR9## wherein each of R¹⁰ and R¹¹, whichmay be the same or different, is C₁ -C₆ alkyl; and

a group of formula (E): ##STR10## wherein s is 0 or 1 and each r, whichmay be the same or different, is 1, 2 or 3 and L is a heterocyclic groupof formula (1) as defined above;

and R² is hydrogen or a group of formula --COR³ as defined aboveprovided that one of R¹ and R² is hydrogen and the other is nothydrogen; or a pharmaceutically acceptable salt thereof.

An alkyl group may be linear or branched. A C₁ -C₆ alkyl group istypically a C₁ -C₄ alkyl group, for example a methyl, ethyl, propyl,i-propyl, n-butyl, sec-butyl or tert-butyl group. A C₁ -C₆ alkoxy groupis typically a C₁ -C₄ alkoxy group, for example a methoxy, ethoxy,propoxy, i-propoxy, n-butoxy, sec-butoxy or tert-butoxy group.

When R¹ is a group of formula --(NH)_(t) --COR³, t may be 0 in whichcase the group has the formula --COR³. The integer v in formula (A) isthen 1. When R³ is a group of formula (A), n is typically 1 and m is 0,1, 2 or 3, or n is 0 and m is 2. R⁴ and R⁵ may be as defined under (a),in which case R⁴ is preferably C₁ -C₆ alkyl, for instance methyl. R⁵ ispreferably C₁ -C₆ alkyl, for instance methyl or ethyl, eitherunsubstituted or substituted on the terminal carbon atom by one or twophenyl groups. These phenyl groups are in turn unsubstituted orsubstituted by one or two methoxy groups. For instance, R⁵ may be adiphenylmethyl, 2-2-diphenylethyl or 3,4-dimethoxyphenethyl group.Alternatively, R⁴ and R⁵ may be as defined under (b). When R⁴ and R⁵together form the heterocyclic ring (1), R⁶ and R⁷ are typically thesame, and are preferably hydrogen or methoxy, or together form amethylenedioxy group. When R⁴ and R⁵ together form the heterocyclic ring(2), Y is O or --NR⁸ wherein R⁸ is preferably methyl, phenyl or3-trifluoromethylphenyl.

When R³ is a group of formula (B), Z is preferably ethenyl, prop-1-enylor prop-2-enyl, or a phenyl group substituted by one or two C₁ -C₆alkoxy groups, preferably methoxy groups. Preferably the phenyl ring is3,4-disubstituted by methoxy groups.

When R³ is a group of formula (C), R⁹ is preferably selected frommethyl, ethyl, pyrimidinyl and phenyl, the phenyl being monosubstitutedat position 2, 3 or 4 by C₁ -C₆ alkoxy, for instance methoxy, and morepreferably being a 4-methoxyphenyl group.

When R¹ is a group of formula (D) R¹⁰ and R¹¹ are typically the same andare preferably both methyl. When R¹ is a group of formula (E), s may be0 in which case the group has the formula --(CH₂)_(r) --L. In formula(E) the substituents R⁶ and R⁷ in the heterocyclic ring are typicallythe same and are preferably both H or methoxy, or together form amethylenedioxy group.

In a first embodiment of formula (I) in which t=1 and v=0, R¹ ishydrogen and R² is a group of formula --COR³ as defined above in whichR³ is a group of formula A.

In a second embodiment of formula (I) R² is hydrogen and R¹ is a groupof formula --COR³ as defined above in which R³ is a group of formula(A), a group of formula (B) wherein Z is ethenyl or phenyl substitutedby two C₁ -C₆ alkoxy groups, or a group of formula (C) wherein R² ismethyl, pyrimidinyl or phenyl. Phenyl substituted by two C₁ -C₆ alkoxygroups is preferably 3,4-dimethoxyphenyl.

In formula (A) in the first and second embodiments described above it ispreferred that n is 0 and m is 2, or n is 1 and m=0, 1 or 2, and either:

(a) R⁴ is C₁ -C₆ alkyl and R⁵ is C₁ -C₆ alkyl substituted on theterminal C atom by 2 unsubstituted phenyl groups or by one phenyl groupwhich is disubstituted by C₁ -C₆ alkoxy groups; or

(b) R⁴ and R⁵ form together with the nitrogen atom to which they areattached a heterocyclic group selected from groups of formulae (1)wherein R⁶ and R⁷ are both H or both C₁ -C₆ alkoxy, or wherein R⁶ and R⁷together form a methylenedioxy group; (2) wherein Y is O or --NR⁸wherein R⁸ is methyl, phenyl or trifluoromethylphenyl; (3); and (4).

Preferably R⁴ is methyl and R⁵ is diphenylmethyl or2-(3,4-dimethoxyphenyl)ethyl, or R⁴ and R⁵ together form insteadheterocyclic ring (1) in which R⁶ and R⁷ are both H or both OMe, ortogether form a methylenedioxy group.

Examples of preferred compounds of formula (I) are as follows:

1-(4-((3Z,6Z)-6-Benzylidene-1-methyl-2,5-dioxo-3-piperazinylidene)methylbenzoyl)-4-(2-pyrimidyl)piperazine(9022);

1-(4-((3Z,6Z)-6-Benzylidene-1-methyl-2,5-dioxo-3-piperazinylidene)methylbenzoyl)-4-methylpiperazine,hydrochloride (9052);

1-(4-((3Z,6Z)-6-Benzylidene-1-methyl-2,5-dioxo-3-piperazinylidene)methylbenzoyl)-4-(4-methoxyphenyl)piperazine,hydrochloride (9071);

N-Allyl-4-((3Z,6Z)-6-benzylidene-1-methyl-2,5-dioxo-3-piperazinylidene)methylbenzamide(9070);

N-(2-Diphenylmethylmethylaminoethyl)-4-((3Z,6Z)-6-benzylidene-1-methyl-2,5-dioxo-3-piperazinylidene)methylbenzamide,hydrochloride (9076);

N-(2-(1,2,3,4-Tetrahydro-2-isoquinolyl)ethyl)-4-((3Z,6Z)-6-benzylidene-1-methyl-2,5-dioxo-3-piperazinylidene)methylbenzamide,hydrochloride (9116);

N-(3,4-Dimethoxyphenethyl)-4-((3Z,6Z)-6-benzylidene-1-methyl-2,5-dioxo-3-piperazinylidene)methylbenzamide(9117);

N-(4-(4-Phenyl-1-piperazinyl)methylphenyl)-4-((3Z,6Z)-6-benzylidene-1-methyl-2,5-dioxo-3-piperazinylidene)methylbenzamide,hydrochloride (9104);

N-(2-(4-Methyl-1-piperazinyl)ethyl)-4-((3Z,6Z)-6-benzylidene-1-methyl-2,5-dioxo-3-piperazinylidene)methylbenzamide(9007);

N-(2-Morpholinoethyl)-4-((3Z,6Z)-6-benzylidene-1-methyl-2,5-dioxo-3-piperazinylidene)methylbenzamide,hydrochloride (9053);

N-(4-Morpholinophenyl)-4-((3Z,6Z)-6-benzylidene-1-methyl-2,5-dioxo-3-piperazinylidene)methylbenzamide,hydrochloride (9054);

N-(4-(2-(1,2,3,4-Tetrahydro-β-carbolin-2-yl)ethyl)phenyl)-4-((3Z,6Z)-6-benzylidene-1-methyl-2,5-dioxo-3-piperazinylidene)methylbenzamide(9080);

N-(4-(1,2,3,4-Tetrahydro-β-carbolin-2-yl)methylphenyl)-4-((3Z,6Z)-6-benzylidene-1-methyl-2,5-dioxo-3-piperazinylidene)methylbenzamide(9096);

N-(4-(2-(4-Phenyl-1-piperazinyl)ethyl)phenyl)-4-((3Z,6Z)-6-benzylidene-1-methyl-2,5-dioxo-3-piperazinylidene)methylbenzamide(9103);

N-(4-(2-(1,2,3,4-Tetrahydro-2-isoquinolyl)ethyl)phenyl)-4-((3Z,6Z)-6-benzylidene-1-methyl-2,5-dioxo-3-piperazinylidene)methylbenzamide(9065);

N-(4-(2-(4-(3-Trifluoromethylphenyl)-1-piperazinyl)ethyl)phenyl)-4-((3Z,6Z)-6-benzylidene-1-methyl-2,5-dioxo-3-piperazinylidene)methylbenzamide(9049);

N-(4-(2-(4-(4-Chlorophenyl)-4-hydroxypiperidino)ethyl)phenyl)-4-((3Z,6Z)-6-benzylidene-1-methyl-2,5-dioxo-3-piperazinylidene)methylbenzamide(9079);

N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)-4-((3Z,6Z)-6-benzylidene-1-methyl-2,5-dioxo-3-piperazinylidene)methylbenzamide(9006);

N-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)-4-((3Z,6Z)-6-benzylidene-1-methyl-2,5-dioxo-3-piperazinylidene)methylbenzamide(9008);

N-(4-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)methylphenyl)-4-((3Z,6Z)-6-benzylidene-1-methyl-2,5-dioxo-3-piperazinylidene)methylbenzamide,hydrochloride (9064);

(3Z,6Z)-6-Benzylidene-3-(4-(3-dimethylamino-2-hydroxypropoxy)benzylidene)-1-methyl-2,5-piperazinedione(9023);

(3Z,6Z)-6-Benzylidene-3-(4-(2-(6,7-dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)benzylidene)-1-methyl-2,5-piperazinedione(9115);

N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)-3-((3Z,6Z)-6-benzylidene-1-methyl-2,5-dioxo-3-piperazinylidene)methylbenzamide,hydrochloride (9051);

N-(4-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)methylphenyl)-3-((3Z,6Z)-6-benzylidene-1-methyl-2,5-dioxo-3-piperazinylidene)methylbenzamide(9128);

N-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)-3-((3Z,6Z)-6-benzylidene-1-methyl-2,5-dioxo-3-piperazinylidene)methylbenzamide(9136);

N-(2-(3,4-Dimethoxyphenethyl)methylamino)ethyl)-3-((3Z,6Z)-6-benzylidene-1-methyl-2,5-dioxo-3-piperazinylidene)methylbenzamide(9137);

N-(4-(2-(3,4-Dimethoxyphenethyl)methylamino)ethyl)phenyl)-3-((3Z,6Z)-6-benzylidene-1-methyl-2,5-dioxo-3-piperazinylidene)methylbenzamide(9138);

N-(4-(2-(4-Phenyl-1-piperazinyl)ethyl)phenyl)-3-((3Z,6Z)-6-benzylidene-1-methyl-2,5-dioxo-3-piperazinylidene)methylbenzamide(9083);

N-(4-(3-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)propyl)phenyl)-3-((3Z,6Z)-6-benzylidene-1-methyl-2,5-dioxo-3-piperazinylidene)methylbenzamide,hydrochloride (9161);

N-(2-(2,2-Diphenylethyl)methylaminoethyl)-3-((3Z,6Z)-6-benzylidene-1-methyl-2,5-dioxo-3-piperazinylidene)methylbenzamide(9163);

(3Z,6Z)-6-Benzylidene-3-(4-(4-(2-(6,7-dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)benzyloxy)benzylidene)-1-methyl-2,5-piperazinedione(9176);

(3Z,6Z)-6-Benzylidene-3-(3-(4-(2-(6,7-dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)benzyloxy)benzylidene)-1-methyl-2,5-piperazinedione(9177);

N-(4-((3Z,6Z)-6-Benzylidene-1-methyl-2,5-dioxo-3-piperazinylidene)methylphenyl)-4-(2-(6,7-dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)benzamide(9190);

1-(4-((3Z,6Z)-6-Benzylidene-1-methyl-2,5-dioxo-3-piperazinylidene)methylbenzoyl)-4-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolyl)methylpiperidine(9200);

Compounds of formula (I) are produced by a process which comprisestreating 1-acetyl-3-benzylidene-4-methyl-2,5-piperazinedione, which hasthe formula (II): ##STR11## with an aldehyde of the following formula(III): ##STR12## wherein R¹ and R² are as defined for formula (I), in anorganic solvent in the presence of a base; and, if desired, convertingthe resulting compound into a pharmaceutically acceptable salt thereof.

Suitable bases include caesium carbonate, sodium carbonate, potassiumcarbonate, sodium hydride, potassium t-butoxide and triethylamine.

Suitable organic solvents include dimethylformamide (DMF),tetrahydrofuran (THF) and in the case of potassium t-butoxide, t-butanoland mixtures thereof.

When DMF is used as solvent the temperature is typically between 0° C.and reflux temperature, for example from 80° C. to 95° C. when caesiumcarbonate is used as base.

When sodium hydride or potassium t-butoxide is used as the base thereaction mixture is typically warmed from 0° C. to room temperature orto 40° C.

The duration of the reaction may be from 1 to 4 hours, for example from2 to 3 hours.

The compound of formula (II) may be prepared as described in ReferenceExample 1 which follows. Compounds of formula (III) may be prepared fromcommercially available starting materials by conventional methods, theparticular starting material and method employed depending upon theidentity of the aldehyde. For instance, an aldehyde of formula (III)wherein one of R¹ and R² is hydrogen and the other is a group of formula--COR³ as defined above may be prepared by a process which comprisestreating a compound of formula (IV): ##STR13## wherein one or R¹¹ andR²¹ is hydrogen and the other is --COOH, --COX wherein X is a halogen,or --CO(OCOR') wherein R' is C₁ -C₆ alkyl, with an amine of formula

    H--R.sup.3

wherein R³ is as defined above, in an inert organic solvent; thereaction being performed in the presence of a coupling agent when R¹¹ orR²¹ is --COOH.

Suitable coupling agents for use when R¹¹ or R¹² is --COOH include1,3-dicyclohexylcarbodiimide,1-cyclohexyl-3-(2-morpholinoethyl)carbodiimide metho-p-toluenesulphonateand 2-chloro-1-methylpyridinium iodide.

When R¹¹ or R²¹ is a group --COX or --CO(OCOR') as defined above, thereaction is optionally conducted in the presence of a base, for instancea tertiary amine such as Et₃ N, or pyridine. The solvent is thensuitably dichloromethane.

The activated compounds of formula (IV) wherein R¹¹ or R²¹ is --COX or--CO(OCOR') may be prepared from the correspondingly compound of formula(IV) wherein R¹¹ or R²¹, respectively, is the carboxy group --COOH byconventional methods which are routine in organic synthesis.

For instance, compounds wherein R¹¹ or R²¹ is --COX may be prepared bytreating the carboxy compound with a halogenating agent, for example achlorinating agent such as SOCl₂, PCl₃, oxalyl chloride or PCl₅.

Compounds wherein R¹¹ or R²¹ is --CO(OCOR') may be prepared by treatingthe carboxy compound with a C₁ -C₆ alkyl haloformate in the presence ofa tertiary amine, for instance EtOCOCl or iBuOCOCl in the presence ofEt₃ N. In this case it is generally convenient to treat the resultingmixture directly with the amine H--R³.

When R³ is a group of formula (A) as defined above in which n is 1 and vis 1, the amine H--R³ may be prepared by reducing the correspondingnitro compound of formula (V): ##STR14## wherein m, R⁴ and R⁵ are asdefined above for formula (A). The reduction may suitably be performedusing iron powder and concentrated hydrochloric acid in methanol,typically under reflux. Alternatively, the reduction may be performedusing hydrogen over a palladium on carbon catalyst.

A compound of formula (V) may be prepared by treating a compound of thefollowing formula (VI): ##STR15## wherein m is as defined in formula (V)and X is a halogen, with an amine of formula (VII): ##STR16## wherein R⁴and R⁵ are as defined above for formula (A), in an organic solvent inthe presence of base. The organic solvent is typically DMF oracetonitrile, and the base is typically K₂ CO₃. The temperature istypically from room temperature to 100° C., for instance from 60° C. to80° C. The duration of the reaction is usually from 1 to 30 hours, forinstance 2 to 24 hours, typically from about 8 hours to about 12 hours.

When R³ is a group of formula (A) as defined above in which n is 0 and vis 1, the amine H--R³ may be prepared by reducing the correspondingnitrile of formula (VIII): ##STR17## wherein m is 1, 2 or 3 and R⁴ andR⁵ are as defined above for formula (A). The reduction may suitably beperformed with LiAlH₄ in ethylene glycol dimethyl ether, at atemperature between 0° C. and 40° C., typically warming from 0° C. toroom temperature, for instance from 0° C. to 20° C. Other amines H--R³may be prepared by analogous methods using known starting materials, orare commercially available products.

A nitrile of formula (VIII) may be prepared by treating a compound offormula (VII) as defined above with a compound of formula (X): ##STR18##wherein X is a halogen and m is as defined for formula (VIII), in anorganic solvent in the presence of a base. The solvent is suitablyacetonitrile. The base may be, for example, K₂ CO₃. The reaction istypically carried out at the reflux temperature of the solvent for aperiod of from 1 hour to 30 hours, for instance from 1 hour to 20 hours.

An aldehyde of formula (III) wherein R¹ is a group of formula (D) may beprepared by treating the compound of formula (XI): ##STR19## with anamine of formula H--N(R¹⁰) (R¹¹) wherein R¹⁰ and R¹¹ are as defined forformula (D), in a suitable solvent. Such solvents include aqueous THF.The compound of formula (XI) may in turn be prepared by treatment of4-hydroxybenzaldehyde with 1.5M sodium hydroxide followed byepichlorohydrin. This reaction is typically performed at about 50° C.for about 5 hours.

The aldehyde of formula (III) wherein R¹ is a group of formula (E) inwhich r is 2 (compound 5.1) may be prepared as described in ReferenceExample 5 which follows. Corresponding aldehydes in which r in formula(E) is 1 or 3 may be prepared by an analogous process, replacing the4-(2-bromoethyl)benzoic acid used as starting material by4-bromomethylbenzoic acid or 4-(3-bromopropyl)benzoic acid,respectively.

An aldehyde of formula (III) may also be prepared by treating thecorresponding nitrile of formula (XII) ##STR20## with formic acid andRaney nickel, for instance as described in Reference Example 7 whichfollows.

Compounds of formula (I) may be converted into pharmaceuticallyacceptable salts, and salts may be converted into the free compound, byconventional methods. Suitable salts include salts with pharmaceuticallyacceptable inorganic or organic acids. Examples of inorganic acidsinclude hydrochloric acid, sulphuric acid and orthophosphoric acid.Examples of organic acids include p-toluenesulphonic acid,methanesulphonic acid, mucic acid and succinic acid.

Cancer cells which exhibit multi-drug resistance, referred to as MDRcells, display a reduction in intracellular drug accumulation comparedwith the corresponding drug-sensitive cells. Studies using in vitroderived MDR cell lines have shown that MDR is often associated withincreased expression of a plasma membrane glycoprotein (P-gp) which hasdrug binding properties. P-gp is thought to function as an efflux pumpfor many hydrophobic compounds, and transfection studies using clonedP-gp have shown that its overexpression can confer the MDR phenotype oncells: see, for example, Ann. Rev. Biochem 58 137-171 (1989).

A major function of P-gp in normal tissues is to export intracellulartoxins from the cell. There is evidence to suggest that overexpressionof P-gp may play a clinical role in multi-drug resistance. Increasedlevels of P-gp mRNA or protein have been detected in many forms of humancancers--leukaemias, lymphomas, sarcomas and carcinomas. Indeed, in somecases P-gp levels have been found to be increased in tumour biopsiesobtained after relapse from chemotherapy.

Inhibition of P-gp function in P-gp mediated MDR has been shown to leadto a net accumulation of anti-cancer agent in the cells. For example,Verapamil a known calcium channel blocker was shown to sensitise MDRcells to Vinca alkaloids in vitro and in vivo: Cancer Res., 41,1967-1972 (1981). The proposed mechanism of action involves competitionwith the anti-cancer agent for binding to the P-gp. A range ofstructurally unrelated resistance-modifying agents acting by thismechanism have been described such as tamoxifen (Nolvadex:ICI) andrelated compounds, and cyclosporin A and derivatives.

Compounds of formula I and their pharmaceutically acceptable salts(hereinafter referred to as "the present compounds") have been found inbiological tests to have activity in modulating multi-drug resistance.The results are set out in Example 3 which follows. The presentcompounds may therefore be used as multi-drug resistance modifyingagents, also termed resistance-modifying agents, or RMAS. The presentcompounds can modulate, e.g. reduce, or eliminate multi-drug resistance.

The present compounds can therefore be used in a method of potentiatingthe cytotoxicity of an agent which is cytotoxic to a tumour cell. Such amethod comprises, for instance, administering one of the presentcompounds to the tumour cell whilst the tumour cell is exposed to thecytotoxic agent in question. The therapeutic effect of achemotherapeutic, or antineoplastic, agent may thus be enhanced. Themulti-drug resistance of a tumour cell to a cytotoxic agent duringchemotherapy may be reduced or eliminated.

The present compounds can also be used in a method of treating a diseasein which the pathogen concerned exhibits multi-drug resistance, forinstance multi-drug resistant forms of malaria (Plasmodium falciparum),tuberculosis, leishmaniasis and amoebic dysentery. Such a methodcomprises, for instance, administering one of the present compounds with(separately, simultaneously or sequentially) the drug to which thepathogen concerned exhibits multi-drug resistance. The therapeuticeffect of the drug may thus be enhanced.

A human or animal patient harbouring a tumour may be treated forresistance to a chemotherapeutic agent by a method comprising theadministration thereto of one of the present compounds. The presentcompound is administered in an amount effective to potentiate thecytotoxicity of the said chemotherapeutic agent. Examples ofchemotherapeutic or antineoplastic agents which are preferred in thecontext of the present invention include Vinca alkaloids such asvincristine and vinblastine; anthracycline antibiotics such asdaunorubicin and doxorubicin; mitoxantrone; actinomycin D; taxanes e.g.taxol; epipodophyllotoxins e.g. etopoposide and plicamycin.

In addition, a human or animal patient suffering from a disease in whichthe responsible pathogen exhibits multi-drug resistance may be treatedfor resistance to a therapeutic agent by a method comprising theadministration thereto of one of the present compounds.

Examples of such disease include multi-drug resistant forms of malaria(Plasmodium falciiparum), tuberculosis, leishmaniasis and amoebicdysentery.

MDR modulators also have utility in the delivery of drugs across theblood-brain barrier, and in the treatment of AIDS and AIDS-relatedcomplex. The present compounds car therefore be used in a method offacilitating the delivery of drugs across the blood brain barrier, andin the treatment of AIDS or AIDS-related complex. A human or animalpatient in need of such treatment may be treated by a method comprisingthe administration thereto of one of the present compounds.

The present compounds can be administered in a variety of dosage forms,for example orally such as in the form of tablets, capsules, sugar- orfilm-coated tablets, liquid solutions or suspensions or parenterally,for example intramuscularly, intravenously or subcutaneously. Thepresent compounds may therefore be given by injection or infusion.

The dosage depends on a variety of factors including the age, weight andcondition of the patient and the route of administration. Typically,however, the dosage adopted for each route of administration when acompound of the invention is administered alone to adult humans is 0.001to 50 mg/kg, most commonly in the range of 0.01 to 5 mg/kg, body weight.Such a dosage may be given, for example, from 1 to 5 times daily bybolus infusion, infusion over several hours and/or repeatedadministration.

A piperazinedione derivative of formula (I) or a pharmaceuticallyacceptable salt thereof is formulated for use as a pharmaceutical orveterinary composition also comprising a pharmaceutically orveterinarily acceptable carrier or diluent. The compositions aretypically prepared following conventional methods and are administeredin a pharmaceutically or veterinarily suitable form. An agent for use asa modulator of multi-drug resistance comprising any one of the presentcompounds is therefore provided.

For example, the solid oral forms may contain, together with the activecompound, diluents such as lactose, dextrose, saccharose, cellulose,corn starch or potato starch; lubricants such as silica, talc, stearicacid, magnesium or calcium stearate and/or polyethylene glycols; bindingagents such as starches, arabic gums, gelatin, methylcellulose,carboxymethylcellulose, or polyvinyl pyrrolidone; disintegrating agentssuch as starch, alginic acid, alginates or sodium starch glycolate;effervescing mixtures; dyestuffs, sweeteners; wetting agents such aslecithin, polysorbates, lauryl sulphates. Such preparations may bemanufactured in known manners, for example by means of mixing,granulating, tabletting, sugar coating, or film-coating processes.

Liquid dispersions for oral administration may be syrups, emulsions andsuspensions. The syrups may contain as carrier, for example, saccharoseor saccharose with glycerol and/or mannitol and/or sorbitol. Inparticular, a syrup for diabetic patients can contain as carriers onlyproducts, for example sorbitol, which do not metabolise to glucose orwhich only metabolise a very small amount to glucose. The suspensionsand the emulsions may contain as carrier, for example, a natural gum,agar, sodium alginate, pectin, methylcellulose, carboxymethylcelluloseor polyvinyl alcohol.

Suspensions or solutions for intramuscular injections may contain,together with the active compound, a pharmaceutically acceptable carriersuch as sterile water, olive oil, ethyl oleate, glycols such aspropylene glycol, and, if desired, a suitable amount of lidocainehydrochloride. Some of the present compounds are insoluble in water.Such compounds may be encapsulated within liposomes.

The invention will be further illustrated in the Examples which follow.

REFERENCE EXAMPLE 1 1-acetyl-3-benzylidene-4-methyl-2,5-piperazinedione

1,4-Diacetyl-2,5-piperazinedione (described by Marcuccio and Elix inAust. J. Chem, 1984, 37, 1791) (25.0 g, 126 mmol) was treated at 130° C.in DMF (200 ml) with triethylamine (17.6 ml, 126 mmol) and benzaldehyde(13.0 ml, 126 mmol). After 4 hours the mixture was cooled to roomtemperature and poured into EtOAc (1000 ml) and washed 3 times withbrine. Any solid formed at this stage was filtered off. The filtrate wasdried (MgSO₄) and the solvent removed in vacuo. The residue wasrecrystallised from EtOAc:Hexane to give 11.78 g (38%) of1-acetyl-3-benzylidene-2,5-piperazinedione.

The latter compound was treated with NaH and MeI in DMF: THF (1:5) at atemperature of 0° C. and allowed to warm to room temperature to give thetitle compound in 57% yield.

REFERENCE EXAMPLE 2 Preparation of Amines H--R³ via SubstitutedNitrobenzene ##STR21##

4-Bromoethyl nitrobenzene (2a) was treated with 1-phenylpiperazine (2b)in the presence of K₂ CO₃ in DMF at 80° C. for 8 hours. Compound 2c wasobtained in 58% yield. 2c was then reduced by treatment with iron powderand concentrated HCl in MeOH under reflux for 3 hours. The desired amine2.1 was obtained in 40% yield.

Following an analogous synthetic route, but using where necessary4-bromomethylnitrobenzene or 4-(3-bromopropyl)nitrobenzene in place of4-(2-bromoethyl)nitrobenzene (2a), and replacing 4-phenylpiperazine (2b)by the appropriate compound of formula (VII), further amines H--R³ wereprepared as shown in Table 1. The conditions employed at each stage inthe preparation of these further amines were as described above foramine 2.1, except for amine 2.9 where the reduction step was conductedusing hydrogen at 50 p.s.i. over palladium on carbon, in ethanol. Thisreduction was performed for 2.5 hours at room temperature. In the caseof amine 2.4, reduction of the nitro group was accompanied byhydrogenolysis of the 4-chlorophenyl group to give the amine 2.4.

    TABLE 1      -      ##STR22##     1  Compound VII Amine H--R.sup.3 (N.sup.o)      2      ##STR23##     2      ##STR24##     1      2      ##STR25##     3      ##STR26##     2      2      ##STR27##     4      ##STR28##     3      2      ##STR29##     5      ##STR30##     4      1      ##STR31##     6      ##STR32##     5      1      ##STR33##     7      ##STR34##     6      1      ##STR35##     8      ##STR36##     7      2      ##STR37##     9      ##STR38##     8      3      ##STR39##      ##STR40##     9

REFERENCE EXAMPLE 3 Preparation of Amines H--R³ via Substituted Nitrile##STR41##

6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (3a) wastreated with chloroacetonitrile in the presence of K₂ CO₃ inacetonitrile under reflux for 24 hours. Compound 3b was obtained in 92%yield. 3b was then treated with LiAlH₄ in ethylene glycol dimethyl etherat room temperature overnight. The temperature was then raised to 40° C.and the reaction continued for 30 minutes. The desired amine 3.1 wasobtained in 98% yield.

Following an analogous synthetic route, but modifying the conditions ofthe first step where necessary and replacing compound 3a by theappropriate compound of formula VII, the further amines H--R³ listed inTable 2 were prepared:

                                      TABLE 2    __________________________________________________________________________    Compound of        Conditions of    formula VII        first step                                Amine H--R.sup.3 (No)    __________________________________________________________________________     ##STR42##    0                   K.sub.2 CO.sub.3, ClCH.sub.2 CN, CH.sub.3 CN reflux                       20 h                                5 #STR43##    1 #STR44##          K.sub.2 CO.sub.3 ClCH.sub.2 CN, CH.sub.3 CN reflux,                       24 h                                6 #STR45##    2 #STR46##          K.sub.2 CO.sub.3 ClCH.sub.2 CN, CH.sub.3 CN reflux 24                       h                                7 #STR47##    3 #STR48##          K.sub.2 CO.sub.3 ClCH.sub.2 CN, CH.sub.3 CN reflux 24                       h                                8 #STR49##    4 #STR50##          K.sub.2 CO.sub.3, ClCH.sub.2 CN CH.sub.3 CN reflux 4                       h                                9 #STR51##    __________________________________________________________________________

REFERENCE EXAMPLE 4 Preparation of Further Amines H--R³

1. (3,4-Dimethoxyphenethyl)Methylamine ##STR52##

2-(3,4-Dimethoxyphenyl)ethylamine (4a) was treated with MeOCOl in thepresence of triethylamine in CH₂ Cl₂ at -78° C. and allowed to warm to0° C. overnight. Compound 4b was obtained in 9% yield. 4b was treatedwith LiAlH₄ in THF at a temperature of 0° C. and allowed to warm to roomtemperature overnight. Compound 4.1, which is the starting amine used toprepare compound 2.9 in Reference Example 2, was obtained in 91% yield.

2. H₂ N--(CH₂)₂ --NMe--CH₂ CHPh₂

2,2-Diphenylethylamine was treated with (CF₃ CO)₂ O in Et₂ O at 0° C.for 1 hour. The resulting compound (Ph)₂ --CH--CH₂ --NHCOCF₃, obtainedin quantitative yield, was treated with KH in THF at 0° C. followed byMeI and 18-crown-6 at room temperature for 24 hours to give (Ph)₂--CH--CH₂ --NMeCOCF₃ in 91% yield. The latter compound was treated with2M NaOH in methanol under reflux for 2 hours to give (Ph)₂ --CH--CH₂NHMe in 81% yield, which in turn was treated with chloroacetonitrile inthe presence of K₂ CO₃ in acetonitrile under reflux for 24 hours to give(Ph)₂ --CH--CH₂ --NMe--CH₂ CN in 83% yield. Reduction of this compoundwith LiAlH₄ in ethylene glycol dimethyl ether at room temperature for 2hours gave the title amine, which is compound 4.2, in 90% yield.

3. Amine 4.3 ##STR53##

Compound 4c was treated with6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline in CH₂ Cl₂ at 0° C. in thepresence of 2-chloro-1-methylpyridinium iodide and triethylamine. Thesolution was allowed to warm to room temperature overnight. Compound 4d,which was obtained in 93% yield, was treated with trifluoroacetic acidin dichloromethane at room temperature for 30 minutes. Compound 4e wasobtained in 10% yield after trituration with acetone. Compound 4e wastreated with LiAlH₄ in THF at 10° C. and left overnight to warm to roomtemperature. Compound 4.3 was obtained in 75% yield.

REFERENCE EXAMPLE 5 Preparation of Aldehyde 5.1 ##STR54##

Compound 5a was treated with excess CH₂ N₂ in THF at 0° C. for 7 hours.5b was obtained in 98% yield. Compound 5b was then treated with6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride in DMF in thepresence of K₂ CO₃ at room temperature for 5 days to give 5c in 56%yield. Compound 5c was reduced by treatment with LiAlH₄ in THF at roomtemperature for 1 hour to give 5d (80% yield), which in turn was treatedwith pyridinium chlorochromate (PCC) buffered with NaOAc in CH₂ Cl₂ atroom temperature for 16 hours. Compound 5.1 was obtained in 25% yield.

REFERENCE EXAMPLE 6 Preparation of Aldehydes of Formula (III)

Method 1

The aldehydes of formula IIIa listed in Table 3 below were prepared bytreating 3-formylbenzoic acid with the appropriate amine H--R³ (acompound prepared in one of Reference Examples 2 and 3) in CH₂ Cl₂ inthe presence of 2-chloro-1-methylpyridinium iodide at 0° C. The reactionwas allowed to warm to room temperature overnight.

                                      TABLE 3    __________________________________________________________________________    Aldehydes of formula IIIa    2 #STR55##                                          Corresponding    Aldehyde No.           R.sup.3                        amine H--R.sup.3    __________________________________________________________________________    6.1           0 #STR56##                     2.2    6.2           1 #STR57##                     2.1    6.3           3 #STR58##                     2.7    6.4           4 #STR59##                     2.9    6.5           5 #STR60##                     3.5    6.6           6 #STR61##                     3.6    6.29           7 #STR62##                     4.2    __________________________________________________________________________

Method 2

The aldehydes of formula IIIb listed in Table 4 below were prepared bytreating 4-formylbenzoyl chloride with the appropriate amine H--R³ inCH₂ Cl₂ in the presence of triethylamine at 0° C. In the case ofaldehyde 6.32, 4-carboxybenzaldehyde was used in place of4-formylbenzoyl chloride and 2-chloro-1-pyridinium iodide wasadditionally present in the reaction mixture. The reaction was allowedto warm to room temperature overnight. Each amine was either a compoundprepared in one of Reference Examples 2 and 3, or a commerciallyavailable product.

                                      TABLE 4    __________________________________________________________________________    Aldehydes of formula IIIb    8 #STR63##                                          Corresponding    Aldehyde No.           R.sup.3                        amine H--R.sup.3    __________________________________________________________________________    6.7           9 #STR64##                     2.2    6.8           0 #STR65##                     3.2    6.9           1 #STR66##                     3.1    6.10           2 #STR67##                     Commercial product    6.11           3 #STR68##                     Commercial product    6.12           4 #STR69##                     Commercial product    6.13           5 #STR70##                     Commercial product    6.14           6 #STR71##                     Commercial product    6.15           7 #STR72##                     2.7    6.16           8 #STR73##                     2.3    6.17           9 #STR74##                     Commercial product    6.18           0 #STR75##                     Commercial product    6.19           1 #STR76##                     3.3    6.20           2 #STR77##                     2.4    6.21           3 #STR78##                     2.5    6.22           4 #STR79##                     2.8    6.23           5 #STR80##                     2.1    6.24           6 #STR81##                     2.6    6.25           7 #STR82##                     3.4    6.26           8 #STR83##                     Commercial product    6.27           9 #STR84##                      2.10    6.32           0 #STR85##                     4.3    __________________________________________________________________________

Method 3

By treating the compound of formula (XI) defined above in THF withaqueous HNMe₂ at room temperature for about 2 hours, the followingaldehyde of formula (III) was produced in 91% yield: ##STR86## Method 4

Compound 5d, described in Reference Example 5, was treated with4-hydroxybenzaldehyde in THF at 0° C. in the presence oftriphenylphosphine and diethyl azidocarboxylate to give the followingaldehyde of formula (III) in 40% yield: ##STR87##

The above process was repeated, but using 3-hyaroxybenzaldehyde in placeof 4-hydroxybenzaldehyde. The following aldehyde of formula (III) wasproduced in 50% yield: ##STR88##

REFERENCE EXAMPLE 7 Preparation of Aldehyde 7.1 ##STR89##

7a was treated with an excess of SOCl₂ and a catalytic amount of DMF intoluene under reflux for 4 hours. The resulting compound 7b was treatedwith 4-aminobenzonitrile in CH₂ Cl₂ in the presence of triethylamine at0° C. The reaction mixture was warmed to room temperature overnight.Flash chromatography (1:1 hexane:ethyl acetate) gave 7c in 39% yield,which was treated with 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline inthe presence of K₂ CO₃ in acetonitrile under reflux for 18 hours. Flashchromatography (10% methanol in ethyl acetate) gave 7d in 25% yield. 7dwas treated with formic acid and a 50% slurry in water of Raney nickelunder reflux for 2 hours. The aldehyde 7.1 was obtained in 71% yield.

EXAMPLE 1 Preparation of compounds of formula (I)

By treating 1-acetyl-3-benzylidene-4-methyl-2,5-piperazinedione, asdescribed in Reference Example 1, with an aldehyde prepared in one ofReference Examples 5, 6 or 7 in DMF in the presence of Cs₂ CO₃, at atemperature of between 80 and 90° C., the compounds of formula I listedin Table 5 were prepared:

                  TABLE 5    ______________________________________    Aldehyde N.sup.o                 Compound of formula I    ______________________________________    6.7          9006    6.8          9007    6.9          9008    6.10         9022    6.28         9023    6.11         9049    6.1          9051    6.12         9052    6.13         9053    6.14         9054    6.15         9064    6.16         9065    6.17         9070    6.18         9071    6.19         9076    6.20         9079    6.21         9080    6.2          9083    6.22         9096    6.23         9103    6.24         9104    5.1          9115    6.25         9116    6.26         9117    6.3          9128    6.5          9136    6.6          9137    6.4          9138    6.27         9161    6.29         9163    6.30         9176    6.31         9177    7.1          9190    6.32         9200    ______________________________________

Compounds 9052, 9071, 9076, 9116, 9104, 9053, 9054, 9064 and 9051 wereconverted in a final step to their hydrochloride salts, by bubblinggaseous HCl through a solution of each compound in THF. (For thesecompounds the hydrochloride salt rather than the free base was used inthe biological testing described in Example 3).

EXAMPLE 2 Pharmaceutical Composition

Tablets, each weighing 0.15 g and containing 25 mg of a compound of theinvention can be manufactured as follows:

Composition for 10,000 tablets

compound of the invention (250 g)

lactose (800 g)

corn starch (415 g)

talc powder (30 g)

magnesium stearate (5 g)

The compound of the invention, lactose and half of the corn starch aremixed. The mixture is then forced through a sieve 0.5 mm mesh size. Cornstarch (10 g) is suspended in warm water (90 ml). The resulting paste isused to granulate the powder. The granulate is dried and broken up intosmall fragments on a sieve of 1.4 mm mesh size. The remaining quantityof starch, talc and magnesium stearate is added, carefully mixed andprocessed into tablets.

EXAMPLE 3 Testing of Compounds (I) as Modulators of MDR

Materials and Methods

The EMT6 mouse mammary carcinoma cell line and the MDR resistant sublimeAR 1.0 were cultured in RPMI 1640 medium containing 10% foetal calfserum and 2 mM glutamine at 37° C. in 5% CO₂. Cells were passagedbetween 1 in 200 and 1 in 2000 in the case of the parental cell line andbetween 1 in 20 and 1 in 200 in the case of the MDR resistant subline,after trypsinisation (0.25% trypsin, 0.2 gl⁻¹, EDTA).

1. Drug Accumulation Assay

AR 1.0 cells were seeded into 96 well opaque culture plates (CanberraPackard). The assay medium contained a mixture of tritiated Daunorubicin(DNR), a cytotoxic agent, and unlabelled DNR (0.3 μCi/ml; 2 μM).Compounds of formula I were serially diluted in assay medium over arange of concentrations from 5 nM to 100 μM. The cells were incubated at37° C. for 1 hr before washing and determination of cell associatedradioactivity. Results were expressed as % maximum accumulation where100% accumulation is that observed in the presence of the known RMAverapamil at 100 μM. Where possible an IC₅₀ was determined.

The results are set out in the following Table 6.

                  TABLE 6    ______________________________________                  IC.sub.50 (μM)                             Max    Compound No.  Accumulation                             Accumulation    ______________________________________    9006          0.4    9007                     30%    9008          3.0    9022          7.0    9023                     30%    9049                     20%    9051          0.15    9052          100    9053          50    9054                     32%    9064          0.3    9065          6    9070          5    9071          6    9076                     44%    9079          80    9080                     18%    9083          2    9096                     20%    9103                     20%    9104          5    9115          5    9116          4    9117          5    9128          3    9136          0.9    9137          2    9138          0.8    9161                     20%    9163          2.0    9176          1.000    9177          1.750    9190          0.350    9200          1.700    ______________________________________

2. Potention of Doxorubicin Toxicity

Compounds of formula (I) were examined for their ability to potentiatethe toxicity of doxorubicin in AR 1.0 cells. In initial proliferationassays compounds were titrated against a fixed concentration ofdoxorubicin (0.86 μm) which alone is non-toxic to AR 1.0 cells. After afour day incubation with doxorubicin proliferation was measured usingthe colorimetric sulphorhodamine B assay (Skehan et al; J.Natl. CancerInst. 82 pp 1107-1112 (1990)). The results are shown in Table 7.

Compounds which were shown to be able to sensitise AR 1.0 cells to 0.86μM doxorubicin without high innate selected for further study. Cellswere cultured for four days with a titration of doxorubicin (0.01 nm-50μM) in the presence of a fixed concentration of each compound.Proliferation was quantified as described by Skehan et. al, loc cit. TheIC₅₀ (concentration required to reduce proliferation to 50% of theuntreated controls) for doxorubicin alone and with each compound werederived and used to calculate the potentiation index (PI): ##EQU1##

The results are shown in Table 8:

                  TABLE 7    ______________________________________                              Toxicity with                 Compound toxicity                              cytotoxic agent    Compound No. (IC.sub.50 μM)                              (IC.sub.50 μM)    ______________________________________    9006         2            0.04    9008         10           2.0    9022         35           0.8    9023         10           5.0    9049         2            0.2    9051         2            0.01    9053         40           4.0    9054         50           30    9064         2            0.01    9065         2            0.2    9070         40           4.0    9071         6            0.2    9079         2            1.7    9083         3            0.1    9104         40           0.05    9115         60           2.0    9116         8            1    9117         8            3    9128         10           2    9136         13           2    9137         12           4.5    9138         8            1.0    9163         10           0.5    9176         10           0.2    9177         15           0.5    9190         15           0.05    9200         13           0.8    ______________________________________

                  TABLE 8    ______________________________________    Potentiation Indices                 Potentiation index    Compound No. (RMA at 1 μM)    ______________________________________    9006         1000    9022         5    9049         15    9051         2000    9064         750    9065         15    9071         4    9079         3    9104         17    9136         25    9138         333    9163         6.7    9176         300.0    9177         75.0    9190         75.0 (measured at 0.3 μM)                 10.0 (measured at 0.1 μM)                 3.3 (measured at 0.03 μM)                 1.4 (measured at 0.01 μM)    ______________________________________

EXAMPLE 4 Characterisation of the Present Compounds

The compounds and salts prepared in the preceding Examples werecharacterised by mass spectroscopic, microanalytical and proton nmrtechniques. The results are set out in Tables 9 and 10:

                                      TABLE 9    __________________________________________________________________________               Mass spec data                        .sup.1 H nmr data               mass     solvent/       Microanalysis    No.       Mol. Formula               (intensity)                    mode                        field                             δ     Calc                                            Found    __________________________________________________________________________    9023       C.sub.24 H.sub.27 N.sub.3 O.sub.4               422(100)                    ESI CDCl.sub.3 /                             2.35 (6H,s), 2.41                                       C 68.39                                            68.09                                               68.26                        400 MHz                             (1H,dd), 2.57 (1H,dd),                                       H 6.46                                            6.44                                               6.42                             2.99 (3H,s), 4.02                                       N 9.97                                            9.81                                               9.81                             (2H,m), 4.08 (1H,m),                             7.00-7.03 (3H,m),                             7.28 -7.42 (8H,m),                             7.95 (1H,b)    9052       C.sub.25 H.sub.26 N.sub.4 O.sub.3 HCl               431(100),                    FAB+                        d.sub.6 -DMSO/                             2.75 (3H,s), 2.88                                       C 64.3                                            64.3               331(50)  300 MHz                             (3H,s), 3.10-3.30                                       H 5.85                                            5.80                             (4H,bs), 3.35 (4H,bs),                                       N 12.0                                            11.6                             6.85 (1H,s), 7.12                             (1H,s), 7.32-7.40                             (5H,m), 7.48 (2H,d),                             7.65 (2H,d), 10.30                             (1H.bs)    9054       C.sub.30 H.sub.28 N.sub.4 O.sub.4 HCl               509(40),                    CI  d.sub.6 -DMSO/                             2.96 (3H,s) 3.40                                       C 66.1                                            66.0               508(45), 300 MHz                             (4H,bs), 3.99 (4H,bs),                                       H 5.35                                            5.30               331(35),      6.98 (1H,s), 7.20                                       N 10.3                                            10.3               178(100)      (1H,s), 7.43-7.56                             (7H,m), 7.82 (2H,d),                             7.89 (2H,d), 8.12                             (2H,d) 10.43 (1H,s),                             10.83 (1H,s)    __________________________________________________________________________

                                      TABLE 10    __________________________________________________________________________               Mass spec data                            .sup.1 H nmr data    No.       Mol. Formula               mass (intensity)                        mode                            solvent/field                                     δ    __________________________________________________________________________    9006       C.sub.39 H.sub.38 N.sub.2 O.sub.5               643(100) ESI d.sub.6 -DMSD/400 MHz                                     2.87 (3H,s), 2.89-3.23 (8H,m), 3.73                                     (2x3H,s), 4.20-4.54 (2H,m), 6.78                                     (1H,s),                                     6.82 (1H,s), 6.88 (1H,s), 7.09 (1H,s),                                     7.20-8.07 (13H,m), 10.30 (1H,s), 10.62                                     (1H,s), 11.01 (1H,bs)    9007       C.sub.27 H.sub.31 N.sub.5 O.sub.3               474(100) ESI CDCl.sub.3 /400 MHz                                     2.35 (3H,s), 2.49-2.73 (10H,m), 3.02                                     (3H,s), 3.59 (2H,m), 7.07 (1H,s),                                     7.28-7.44                                     (6H,m), 7.50 (2H,d), 7.86 (2H,d)    9008       C.sub.33 H.sub.34 N.sub.4 O.sub.5               567(100) ESI CDCl.sub.3 /400 MHz                                     2.76-2.90 (6H,m), 3.02 (3H,s),                                     3.61-3.70                                     (4H,m), 3.85 (2x3H,s), 6.55 (1H.s),                                     6.64                                     (1H,s), 6.94 (1H,bs), 7.07 (1H.s),                                     7.27-                                     7.43 (6H,m), 7.47 (2H,d), 7.85 (2H,d)    9022       C.sub.28 H.sub.26 N.sub.6 O.sub.3               495(20), ESI CDCl.sub.3 /400 MHz                                     3.02 (3H,s), 3.35-4.07 (8H,m), 6.56                                     (1H,t),               331(100)              7.08 (1H,s), 7.29-7.43 (6H,m), 7.50                                     (2H,d),                                     7.55 (2H,d) 8.83 (2H,d)    9049       C.sub.39 H.sub.36 F.sub.3 N.sub.5 O.sub.3               680(100) ESI CDCl.sub.3 /400 MHz                                     2.64-2.75 (6H,m), 2.87 (2H,m), 3.04                                     (3H,s),                                     3.23-3.31 (4H,m), 7.04-7.10 (3H,m),                                     7.12                                     (1H,s) 7.23-7.42 (9H,m), 7.55 (2H,d),                                     7.59                                     (2H,d), 7.78 (1H,s), 7.96 (2H,d)    9051       C.sub.39 H.sub.38 N.sub.4 O.sub.5.HCl               643(22), 348(30),                        CI  d.sub.6 -DMSO/400 MHz                                     2.86 (3H,s), 2.92-3.18 (6H m) 3.36-3.48               206(100)              (2H,m), 3.73 (2x3H,s), 4.22-4.55                                     (2H,m),                                     6.78 (1H,s), 6.82 (1H,s), 6.89 (1H,s),                                     7.09                                     (1H,s), 7.28-8.14 (13H,m), 10.29                                     (1H,s),                                     10.69 (2H,bs)    9053       C.sub.26 H.sub.28 N.sub.4 O.sub.4.HCl               461(100), 331(10),                        FAB+                            d.sub.5 -DMSO/300 MHz                                     2.82 (3H,s), 3.05-3.20 (2H,bs),                                     3.45-3.62                                     (2H,bs), 3.68-3.78 (4H,bs), 3.80-3.90                                     (2H,bs), 3.90-4.00 (2H,bs), 6.82                                     (1H,s),                                     7.07 (1H,s), 7.33-7.48 (5H,m), 7.66                                     (2H,d),                                     7.96 (2H,d), 8.80-9.05 (1H,bs), 10.15                                     (1H,s), 10.95-11.15 (1H,bs)    9064       C.sub.38 H.sub.36 N.sub.4 O.sub.5.HCl               629(100) ESI d.sub.6 -DMSO/                                     2.87 (3H.s), 2.90-3.40 (4H,m), 3.70                            400 MHz  (2x3H,s), 4.10-4.52 (4H,m), 6.80                                     (2x1H,s),                                     6.89 (1H,s), 7.11 (1H,s), 7.30-7.45                                     (5H,m),                                     7.59 (2H,d), 7.73 (2H,d), 7.91 (2H,d),                                     8.02                                     (2H,d), 10.46 (1H.s), 10.64 (2H,bs)    9065       C.sub.37 H.sub.34 N.sub.4 O.sub.3               582(10), 449(30),                        CI  CDCl.sub.3 /400 MHz                                     2.65-3.10 (11H,m), 3.74 (2H,s),                                     6.95-8.10               331(100)              (21H,m)    9070       C.sub.23 H.sub.21 N.sub.3 O.sub.3               388(100) CI  CDCl.sub.3 /300 MHz                                     3.05 (3H,s), 4.15 (2H,t), 5.35 (2H,m),                                     5.95                                     (1H,m), 6.24 (1H,bs), 7.10 (1H,s),                                     7.32-                                     7.46 (6H,m), 7.53 (2H,d), 7.90 (2H,d),                                     8.05                                     (1H,bs)    9071       C.sub.31 H.sub.30 N.sub.4 O.sub.4.HCl               523(100),                        FAB+                            d.sub.6 -DMSO/300 MHz                                     2.88 (3H,s), 3.12 (4H,m), 3.69 (4H,m),                                     3.72               331(75), 162(60)      (3H,s), 6.86-6.89 (3H,m), 7.02 (2H,d),                                     7.11                                     (1H,s), 7.35-7.52 (7H,m), 7.63 (2H,d),                                     10.36 (1H,bs) (70° C.)    9076       C.sub.36 H.sub.34 N.sub.4 O.sub.3.HCl               571(35), 196(50),                        CI  CDCl.sub.3 /300 MHz                                     2.7-4.3 (4H,m), 2.90 (3H,s), 3.05                                     (3H,s),               167(100), 108(80)     4.95 (1H,bs) 7.0-8.5 (21H,m), 9.35                                     (1H,bs),                                     11.95 (1H,bs)    9079       C.sub.39 H.sub.38 N.sub.4 O.sub.4               627(5), 156(36),                        CI  d.sub.6 -DMSO/400 MHz                                     1.62 (2H,m), 1.88-2.04 (2H,m),                                     2.40-2.82               85(100)               (8H,m), 2.89 (3H,s), 4.77 (1H,s), 6.87                                     (1H,s), 7.09 (1H,s), 7.17-7.80 (17H,m),                                     8.02 (2H,d), 10.19 (1H,s)    9080       C.sub.39 H.sub.35 N.sub.5 O.sub.3               622(100) ESI d.sub.6 -DMSO/400 MHz                                     2.64-2.90 (8H,m), 2.86 (3H,s), 3.68                                     (2H,s),                                     6.88 (1H,s), 6.90-7.04 (2H,m), 7.10                                     (1H,s),                                     7.22-7.48 (9H,m), 7.72 (4H,m), 8.00                                     (2H,d),                                     10.19 (1H,s), 10.67 (1H,s)    9096       C.sub.38 H.sub.33 N.sub.5 O.sub.3               608(15), 291(100)                        CI  d.sub.6 -DMSO/400 MHz                                     2.74 (3H,s), 2.70 (2H,m), 2.80 (2H,m),                                     3.58                                     (2H,s), 3.70 (2H,s), 6.88 (1H,s),                                     6.90-7.05                                     (2H,m), 7.10 (1H,s), 7.20-7.50 (9H,m),                                     7.65-7.80 (4H,m), 8.00 (2H,d), 10.27                                     (1H,s), 10.62 (1H,s)    9103       C.sub.38 H.sub.37 N.sub.5 O.sub.3               612(87), 175(100)                        CI  d.sub.6 -DMSO/400 MHz                                     2.5-2.6 (6H,m), 2.75 (2H,m), 2.85                                     (3H,s),                                     3.11 (4H,m), 6.75 (1H,t), 6.88 (1H,s),                                     6.90                                     (2H,d), 7.1 (1H,s), 7.2 (3H,m),                                     7.28-7.49                                     (7H,m), 7.75 (3H,m) 8.1 (2H,d), 10.15                                     (1H,s), 10.6 (1H,bs)    9104       C.sub.37 H.sub.35 N.sub.5 O.HCl               598(100) CI  d.sub.6 -DMSO/400 MHZ                                     2.5 (4H,m), 2.85 (3H,s), 3.11 (4H,m),                                     3.5                                     (2H,s), 6.75 (1H,t), 6.88 (1H,s), 6.90                                     (2H,d), 7.1 (1H,s), 7.2 (3H,m),                                     7.28-7.49                                     (7H,m), 7.75 (3H,m), 8.1 (2H,d)    9116       C.sub.31 H.sub.30 N.sub.4 O.sub.3.HCl               507(100) CI  CDCl.sub.3 /300 MHz                                     2.90 (3H,s), 3.0-4.8 (10H,m), 6.86                                     (1H,s),                                     7.11 (1H,s), 7.15-7.50 (9H,m),                                     7.68(2H,d),                                     7.96 (2H,d), 8.77 (1H,bs), 10.34                                     (1H,bs),                                     10.42 (1H,b)    9117       C.sub.30 H.sub.29 N.sub.3 O.sub.5               529(5), 512(100),                        CI  CDCl.sub.3 /300 MHz                                     2.93 (2H,t), 3.05 (3H,s), 23.76 (2H,q),                                     3.90               275(10), 118(20)      (3H,s), 3.92 (3H,s), 6.20 (1H,bt),                                     6.81-                                     6.90 (3H,m), 7.08 (1H,s), 7.30-7.47                                     (6H,m),                                     7.51 (2H,d), 7.81 (2H,d), 8.04 (1H,bs)    9115       C.sub.32 H.sub.33 N.sub.3 O.sub.4               524(95), 190(100)                        CI  d.sub.6 -DMSO/400 MHz                                     2.63-2.72 (4H,m), 2.7 (3H,s), 2.84                                     (4H,bs),                                     3.52 (2H,s), 3.69 (6H,s), 6.61 (1H,s),                                     6.65                                     (1H,s), 6.8 (1H,s), 6.98 (1H,s), 7.07                                     (1H,s), 7.28-7.51 (9H,m)    9161       C.sub.40 H.sub.40 N.sub.4 O.sub.5               657(7)   CI  CDCl.sub.3 /400 MHz                                     1.92 (2H,m), 2.47-2.85 (8H,m), 2.99                                     (3H,s),                                     3.57 (2H,s), 3.85 (2x3H,s), 6.52                                     (1H,s),                                     6.59 (1H,s), 7.10 (1H,s), 7.15-7.60                                     (13H,m), 7.85 (1H,m), 7.98 (1H,s), 8.08                                     (1H,s)    9083       C.sub.38 H.sub.37 N.sub.5 O.sub.3               612(100) ESI CDCl.sub.3 /400 MHz                                     2.62-2.72 (6H,m), 2.82-2.89 (2H,m),                                     2.99                                     (3H,s), 3.25 (4H,m), 6.88 (1H,t), 6.96                                     (2H,d), 7.09 (1H,s), 7.20-7.29 (6H,m),                                     7.32-7.42 (4H,m), 7.53-7.61 (4H,m),                                     7.85                                     (1H,m), 7.97 (1H,s), 8.05 (1H,s), 8.53                                     (1H,bs)    9128       C.sub.38 H.sub.36 O.sub.5 N.sub.4               629(100) ESI CDCl.sub.3 /400 MHz                                     2.74 (m,2H), 2.83 (m.2H), 3.01 (s.3H),                                     3.55                                     (s,2H), 3.69 (s,2H), 3.82 (s,3H), 3.85                                     (s,3H), 6.49 (s,1H), 6.58 (s,1H), 7.09                                     (s,1H), 7.25-7.44 (10H,m), 7.58-7.64                                     (4H,m), 7.92 (1H,s), 7.96 (1H,s)    9136       C.sub.33 H.sub.34 N.sub.4 O.sub.5               567(100) CI  CDCl.sub.3 /400 MHz                                     2.75-2.90 (6H,m), 3.00 (3H,s),                                     3.60-3.72                                     (4H,m), 3.84 (6H,s), 6.54 (1H,s), 6.60                                     (1H,s), 7.03-7.11 (2H,m), 7.24-7.78                                     (10H,m), 7.84 (1H,s)    9137       C.sub.33 H.sub.36 N.sub.4 O.sub.5               569(95), 357(100)                        CI  CDCl.sub.3 /400 MHz                                     2.38 (3H,s), 2.62-2.80 (6H,m), 3.2                                     (3H,s),                                     3.46-3.54 (2H,m), 3.75 (3H,s), 3.81                                     (3H,s),                                     6.60-6.85 (5H,m), 7.6 (1H,s), 7.25-7.55                                     (9H,m) 7.79 (1H,s)    9138       C.sub.39 H.sub.40 N.sub.4 O.sub.5               645(71), 106(100)                        CI  CDCl.sub.3 /400 MHz                                     2.38 (3H,s), 2.60-2.82 (8H,m), 2.96                                     (3H,s),                                     3.85 (2x3H,s), 6.68-6.82 (3H,m),                                     7.04-7.60                                     (14H,m), 7.81 (1H,d), 7.97 (1H,s), 8.07                                     (1H,s)    9155       C.sub.37 H.sub.36 N.sub.4 O.sub.5 S               649(100) ESI CDCl.sub.3 /400 MHz                                     2.72-2.93 (8H,m), 3.19 (3H,s), 3.65                                     (2H,s),                                     3.85 (2x3H,s), 6.54 (1H,s), 6.60                                     (1H,s),                                     7.04 (1H,m), 7.08-7.10 (2H,m),                                     7.22-7.29                                     (3H,m), 7.45 (1Hm), 7.52-7.60 (4H,m),                                     7.81                                     (1H,m), 7.95 (2H,s) 8.38 (1H,s)    9163       C.sub.37 H.sub.36 N.sub.4 O.sub.3               585(100) ESI CDCl.sub.3 /400 MHz                                     2.36(3H,s), 2.65 (2H,t), 2.95-3.10                                     (5H,m),                                     3.45 (2H,d), 4.20 (1H,t), 6.38                                     (1H,brs),                                     7.05-8.20 (22H,m)    9176                    CDCl.sub.3 /400 MHz                                     2.70-2.98 (8H,m), 3.00 (3H,s), 3.65                                     (2H,s),                                     3.82 (2x3H,s), 5.09 (2H,s), 6.53                                     (1H,s),                                     6.61 (1H,s), 7.00-7.10 (4H,m),                                     7.21-7.58                                     (7H,m), 7.82 (2H,d), 7.91 (1H,br s)    9177                    CDCl.sub.3 /400 MHz                                     2.62-2.89 (8H,m), 2.91 (3H,s), 3.57                                     (2H,s),                                     3.76 (2x3H,s), 4.97 (2H,s), 6.45                                     (1H,s),                                     6.51 (1H,s), 6.82-6.95 (3H,m),                                     7.12-7.38                                     (12H,m), 8.05 (1H,br s)    9190       C.sub.39 H.sub.38 N.sub.4 O.sub.3               643(3)   CI  CDCl.sub.3 /400 MHz                                     2.70-3.04 (11H,m), 3.65 (2H,s), 3.85                                     (2x3H,s), 6.53 (1H,s), 6.60 (1H,s),                                     7.03                                     (1H,s), 7.15-7.50 (11H,m), 7.68-7.92                                     (5H,m)    9200       C.sub.37 H.sub.40 N.sub.4 O.sub.5               620(32)  EI  CDCl.sub.3 /400 MHz                                     1.05-2.00 (9H,m), 2.35-2.45(2Hd), 2.62-                                     2.84 (4H,m), 3.2 (3H,s), 3.55 (2H,s),                                     3.84                                     (2x3H,s), 6.52 (1H,s), 6.60 (1H,s),                                     7.06                                     (1H,s), 7.20-7.55 (11H,m)    __________________________________________________________________________

We claim:
 1. A piperazinedione of general formula (I): ##STR90## whereinR¹ is selected from: hydrogena group of formula --(NH)_(t) --COR³wherein t is 0 and R³ is selected from: ##STR91## wherein v is 1; andwherein n is 0 or 1 and m is 0, 1, 2 or 3, at least one of n and m beingother than 0, and either(a) R⁴ is H or C₁ -C₆ alkyl and R⁵ is C₁ -C₆alkyl optionally substituted by one or two phenyl groups, the phenylgroup or groups being optionally substituted by one or two C₁ -C₆ alkoxygroups; or (b) R⁴ and R⁵, together with the nitrogen atom to which theyare attached, form a heterocyclic group selected from (1) to (4):##STR92## wherein R⁶ and R⁷, which are the same or different, are H orC₁ -C₆ alkoxy, or R⁶ and R⁷ together form a methylenedioxy group; Y is Oor --NR⁸ wherein R⁸ is C₁ -C₆ alkyl or a phenyl group optionallysubstituted by CF₃ ;

    --NH--(CH.sub.2).sub.p --Z                                 (B)

wherein p is 1 or 2 and Z is C₂ -C₆ alkenyl or a phenyl group optionallysubstituted by C₁ -C₆ alkoxy; and ##STR93## wherein R⁹ is C₁ -C₆ alkyl,pyrimidinyl or a phenyl group optionally substituted by C₁ -C₆ alkoxy;##STR94## or R¹ is selected from: a group of the formula (D): ##STR95##wherein each of R¹⁰ and R¹¹, which may be the same or different, is C₁-C₆ alkyl; and a group of formula (E): ##STR96## wherein s is 0, r is 1,2 or 3 and L is a heterocyclic group of formula (1) as defined above;and R² is hydrogen or a group of formula --COR³ as defined above,provided that one of R¹ and R² is hydrogen and the other is nothydrogen; or a pharmaceutically acceptable salt thereof.
 2. A compoundaccording to claim 1 wherein R¹ is hydrogen and R² is a group of formula--COR³ as defined in claim 1 in which R³ is a group of formula A.
 3. Acompound according to claim 1, wherein R² is hydrogen and R¹ is a groupof formula --COR³ as defined in claim 1 in which R³ is a group offormula (A), a group of formula (B) wherein Z is ethenyl or phenylsubstituted by two C₁ -C₆ alkoxy groups, or a group of formula (C)wherein R⁹ is methyl, pyrimidinyl or phenyl.
 4. A compound according toclaim 1 wherein, in formula (A), n is 0 and m is 2, or n is 1 and m is0, 1, 2 or 3, or n is 1 and m is 0, and either(a) R⁴ is C₁ -C₆ alkyl andR⁵ is C₁ -C₆ alkyl substituted on the terminal C atom by 2 unsubstitutedphenyl groups or by one phenyl group which is disubstituted by C₁ -C₆alkoxy groups; or (b) R⁴ and R⁵ form together with the nitrogen atom towhich they are attached a heterocyclic group selected from groups offormula (1) wherein R⁶ and R⁷ are both H or both C₁ -C₆ alkoxy, ortogether form a methylenedioxy group; formula (2) wherein Y is O or--NR⁸ wherein R⁸ is methyl, phenyl or trifluoromethylphenyl; formula(3); and formula (4).
 5. A compound according to claim 1 wherein R² ishydrogen and R¹ is a group of formula (D) or (E) as defined in claim 1.6. A compound selectedfrom:1-(4-((3Z,6Z)-6-Benzylidene-1-methyl-2,5-dioxo-3-piperazinylidene)methylbenzoyl)-4-(2-pyrimidyl)piperazine(9022);1-(4-((3Z,6Z)-6-Benzylidene-1-methyl-2,5-dioxo-3-piperazinylidene)methylbenzoyl)-4-methylpiperazine,hydrochloride (9052);1-(4-((3Z,6Z)-6-Benzylidene-1-methyl-2,5-dioxo-3-piperazinylidene)methylbenzoyl)-4-(4-methoxyphenyl)piperazine,hydrochloride (9071);N-Allyl-4-((3Z,6Z)-6-benzylidene-1-methyl-2,5-dioxo-3-piperazinylidene)methylbenzamide(9070);N-(2-Diphenylmethylmethylaminoethyl)-4-((3Z,6Z)-6-benzylidene-1-methyl-2,5-dioxo-3-piperazinylidene)methylbenzamide,hydrochloride (9076);N-(2-(1,2,3,4-Tetrahydro-2-isoquinloyl)ethyl)-4-((3Z,6Z)-6-benzylidene-1-methyl-2,5-dioxo-3-piperazinylidene)methylbenzamide,hydrochloride (9116);N-(3,4-Dimethoxyphenethyl)-4-((3Z,6Z)-6-benzylidene-1-methyl-2,5-dioxo-3-piperazinylidene)methylbenzamide(9117);N-(4-(4-Phenyl-1-piperazinyl)methylphenyl)-4-((3Z,6Z)-6-benzylidene-1-methyl-2,5-dioxo-3-piperazinylidene)methylbenzamide,hydrochloride (9104);N-(2-(4-Methyl-1-piperazinyl)ethyl)-4-((3Z,6Z)-6-benzylidene-1-methyl-2,5-dioxo-3-piperazinylidene)methylbenzamide(9007);N-(2-Morpholinoethyl)-4-((3Z,6Z)-6-benzylidene-1-methyl-2,5-dioxo-3-piperazinylidene)methylbenzamide,hydrochloride (9053);N-(4-Morpholinophenyl)-4-((3Z,6Z)-6-benzylidene-1-methyl-2,5-dioxo-3-piperazinylidene)methylbenzamide,hydrochloride (9054);N-(4-(2-(1,2,3,4-Tetrahydro-β-carbolin-2-yl)ethyl)phenyl)-4-((3Z,6Z)-6-benzylidene-1-methyl-2,5-dioxo-3-piperazinylidene)methylbenzamide(9080);N-(4-(1,2,3,4-Tetrahydro-β-carbolin-2-yl)methylphenyl)-4-(3Z,6Z)-6-benzylidene-1-methyl-2,5-dioxo-3-piperazinylidene)methylbenzamide(9096);N-(4-(2-(4-Phenyl-1-piperazinyl)ethyl)phenyl)-4-((3Z,6Z)-6-benzylidene-1-methyl-2,5-dioxo-3-piperazinylidene)methylbenzamide(9103);N-(4-(2-(1,2,3,4-Tetrahydro-2-isoquinolyl)ethyl)phenyl)-4-((3Z,6Z)-6-benzylidene-1-methyl-2,5-dioxo-3-piperazinylidene)methylbenzamide(9065);N-(4-(2-(4-(3-Trifluoromethylphenyl)-1-piperazinyl)ethyl)phenyl)-4-((3Z,6Z)-6-benzylidene-1-methyl-2,5-dioxo-3-piperazinylidene)methylbenzamide(9049);N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)-4-((3Z,6Z)-6-benzylidene-1-methyl-2,5-dioxo-3-piperazinylidene)methylbenzamide(9006);N-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)-4-((3Z,6Z)-6-benzylidene-1-methyl-2,5-dioxo-3-piperazinylidene)methylbenzamide(9008);N-(4-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)methylphenyl)-4-((3Z,6Z)-6-benzylidene-1-methyl-2,5-dioxo-3-piperazinylidene)methylbenzamide,hydrochloride (9064);(3Z,6Z)-6-Benzylidene-3-(4-(3-dimethylamino-2-hydroxypropoxy)benzylidene)-1-methyl-2,5-piperazinedione(9023);(3Z,6Z)-6-Benzylidene-3-(4-(2-(6,7-dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)benzylidene)-1-methyl-2,5-piperazinedione(9115);N-(4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)phenyl)-3-((3Z,6Z)-6-benzylidene-1-methyl-2,5-dioxo-3-piperazinylidene)methylbenzamide,hydrochloride (9051);N-(4-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)methylphenyl)-3-((3Z,6Z)-6-benzylidene-1-methyl-2,5-dioxo-3-piperazinylidene)methylbenzamide(9128);N-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)-3-((3Z,6Z)-6-benzylidene-1-methyl-2,5-dioxo-3-piperazinylidene)methylbenzamide(9136);N-(2-(3,4-Dimethoxyphenethyl)methylamino)ethyl)-3-((3Z,6Z)-6-benzylidene-1-methyl-2,5-dioxo-3-piperazinylidene)methylbenzamide(9137);N-(4-(2-((3,4-Dimethoxyphenethyl)methylamino)ethyl)phenyl)-3-((3Z,6Z)-6-benzylidene-1-methyl-2,5-dioxo-3-piperazinylidene)methylbenzamide(9138);N-(4-(2-(4-Phenyl-1-piperazinyl)ethyl)phenyl)-3-((32,6Z)-6-benzylidene-1-methyl-2,5-dioxo-3-piperazinylidene)methylbenzamide(9083);N-(4-(3-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)propyl)phenyl)-3-((3Z,6Z)-6-benzylidene-1-methyl-2,5-dioxo-3-piperazinylidene)methylbenzamide,hydrochloride (9161);N-(2-(2,2-Diphenylethyl)methylaminoethyl)-3-((3Z,6Z)-6-benzylidene-1-methyl-2,5-dioxo-3-piperazinylidene)methylbenzamide(9163);(3Z,6Z)-6-Benzylidene-3-(4-(4-(2-(6,7-dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)benzyloxy)benzylidene)-1-methyl-2,5-piperazinedione(9176);N-(4-((3Z,6Z)-6-Benzylidene-1-methyl-2,5-dioxo-3-piperazinylidene)methylphenyl)-4-(2-(6,7-dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)ethyl)benzamide(9190).
 7. A piperazinedione of general formula (I): ##STR97## whereinR¹ is selected from: hydrogen; anda group of formula --(NH)_(t) --COR³wherein t is 1 and R³ is selected from: ##STR98## wherein v is 0; andwherein n is 0 or 1 and m is 0, 1, 2 or 3, at least one of n and m beingother than 0, and either(a) R⁴ is H or C₁ -C₆ alkyl and R⁵ is C₁ -C₆alkyl optionally substituted by one or two phenyl groups, the phenylgroup or groups being optionally substituted by one or two C₁ -C₆ alkoxygroups; or (b) R⁴ and R⁵, together with the nitrogen atom to which theyare attached, form a heterocyclic group selected from (1) to (4):##STR99## wherein R⁶ and R⁷, which are the same or different, are H orC₁ -C₆ alkoxy, or R⁶ and R⁷ together form a methylenedioxy group; Y is Oor --NR⁸ wherein R⁸ is C₁ -C₆ alkyl or a phenyl group optionallysubstituted by CF₃ ;

    --NH--(CH.sub.2).sub.p --Z                                 (B)

wherein p is 1 or 2 and Z is C₂ -C₆ alkenyl or a phenyl group optionallysubstituted by C₁ -C₆ alkoxy; and ##STR100## wherein R⁹ is C₁ -C₆ alkyl,pyrimidinyl or a phenyl group optionally substituted by C₁ -C₆ alkoxy;and ##STR101## wherein w is 1, 2 or 3 and L is a heterocyclic group offormula (1) as defined above; or R¹ is selected from a group of theformula (D): ##STR102## wherein each of R¹⁰ and R¹¹, which may be thesame or different, is C₁ -C₆ alkyl; and a group of formula (E):##STR103## wherein s is 0 or 1 and each r, which may be the same ordifferent, is 1, 2 or 3 and L is a heterocyclic group of formula (1) asdefined above; and R² is hydrogen or a group of formula --(NH)_(t)--COR³ as defined above, provided that one of R¹ and R² is hydrogen andthe other is not hydrogen; or a pharmaceutically acceptable saltthereof.
 8. A compound according to claim 7 wherein R¹ is hydrogen andR² is a group of formula --(NH)_(t) --COR³ in which R³ is a group offormula A.
 9. A compound according to claim 7 wherein R² is hydrogen andR¹ is a group of formula --(NH)_(t) --COR³ in which R³ is a group offormula --(NH)_(t) --COR³ in which R³ is a group of formula (A), a groupof formula (B) wherein Z is ethenyl or phenyl substituted by two C₁ -C₆alkoxy groups, or a group of formula (C) wherein R⁹ is methyl,pyrimidinyl or phenyl.
 10. A compound according to claim 7, wherein, informula (A), n is 0 and m is 2, or n is 1 and m is 0, 1, 2 or 3, or n is1 and m is 0, and either(a) R⁴ is C₁ -C₆ alkyl and R⁵ is C₁ -C₆ alkylsubstituted on the terminal C atom by 2 unsubstituted phenyl groups orby one phenyl group which is disubstituted by C₁ -C₆ alkoxy groups; or(b) R⁴ and R⁵ form together with the nitrogen atom to which they areattached a heterocyclic group selected from groups of formula (1)wherein R⁶ and R⁷ are both H or both C₁ -C₆ alkoxy, or together form amethylenedioxy group; formula (2) wherein Y is O or --NR⁸ wherein R⁸ ismethyl, phenyl or trifluoromethylphenyl; formula (3); and formula (4).11. A compound according to claim 7 wherein R² is hydrogen and R¹ is agroup of formula (D) or (E) as defined in claim
 7. 12. A pharmaceuticalor veterinary composition which comprises a pharmaceutically orveterinarily acceptable carrier or diluent and, as an active principal,a compound as claimed in claim
 7. 13. A process for producing a compoundas defined in claim 7, which process comprises treating1-acetyl-3-benzylidene-4-methyl-2,5-piperazinedione with an aldehyde offormula (III): ##STR104## wherein R¹ and R² are as defined in claim 1 or7, in an organic solvent in the presence of a base; and, if desired,converting the resulting compound into a pharmaceutically acceptablesalt thereof.
 14. A method of treating resistance to a chemotherapeuticagent in a patient harboring a tumor which method comprisesadministering to a patient in need thereof a therapeutically effectiveamount of a compound as defined in claim 1 or 7 wherein thechemotherapeutic agent is selected from the group consisting ofanthracyline antibiotics, vinca alkaloids, mitoxantrone, actinomycin D,taxanes, epipodophyllotoxins and plicamycin.
 15. A method according toclaim 14 wherein the chemotherapeutic agent is an anthracyclineantiobiotic.
 16. A method according to claim 15 wherein theanthracycline antibiotic is doxorubicin or daunorubicin.
 17. A methodaccording to claim 14, which comprises administering the said compoundto the patient whilst the tumor is exposed to the said chemotherapeuticagent.
 18. A method of modulating P-gp mediated MDR in the treatment oftumors, which method comprises administering to a patient harboring atumor which expresses P-gp mediated MDR a therapeutically effectiveamount of a compound as defined in claim 1 or 7.